Behaviors induced in mice by intrathecal injections of either N-methyl-D-aspartate (NMDA) or kainic acid are modulated by NH2-terminal fragments of substance P, such as substance P-(1-7). The action of substance P-(1-7) on kainic acid depends on σ receptor activity. The present study was designed to test the hypothesis that σ receptor activity is also necessary for modulation of NMDA by substance P-(1-7). Intrathecal injection of mice with NMDA results in a brief burst of biting and scratching behaviors which decrease in intensity when NMDA is injected repeatedly at 2 min intervals. Pretreatment with 1,3-di-O-tolylguanidine (DTG), a ligand at both σ1 and σ2 sites, converted NMDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was without effect, the potentiation of NMDA-induced activity by DTG was abolished by haloperidol but unaffected by an equimolar dose of either spiperone or thiothixine, two dopamine receptor antagonists. When mice received substance P-(1-7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both inhibitory and potentiative effects of substance P-(1-7) whereas thiothixine did not, suggesting inhibitory as well as potentiative modulation of NMDA by σ receptor activity. Endogenous σ1 receptor activity may enhance NMDA receptor activity as a treatment regimen that down-regulates σ1 binding also inhibited responses to NMDA. In contrast, pretreatment with haloperidol just 5 min prior to challenge, which blocks both σ1 and σ2 receptor activity, increased responses to NMDA suggesting an inhibitory effect of σ2 receptor activity. In summary, modulation of NMDA by substance P-(1-7) appears to depend on activity at σ sites as substance P-(1-7) mimicked the potentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1-7).
Bibliographical noteFunding Information:
This research was supported by U.S. Public Health Service Grants DA04090 and DA00124 to A.A.L. The authors wish to thank Dr. Katalin Kovacs for her careful and helpful editorial comments on the manuscript.
- DTG (1,3-di(2-tolyl)guanidine)
- spinal cord, mouse